High Fat Diet and the Colonic Mucus Barrier: Implications for Obesity and Inflammatory Bowel Disease

The prevalence of obesity is increasing at an alarming rate worldwide. Prolonged high fat diets (HFDs) induce low-grade chronic intestinal inflammation in mice, and HFDs are a risk factor for the development of human inflammatory bowel diseases. We hypothesised that during HFD-induced obesity, endoplasmic reticulum (ER) and oxidative stress occurs in intestinal secretory cells, which triggers inflammatory signalling and reduces synthesis and secretion of proteins forming the protective mucus barrier. We comprehensively analysed changes in mucus barrier components, ER/oxidative stress, and inflammation in mice fed HFDs for 3, 11 and 22 weeks. We also examined the effect of suppressing ER stress during a HFD with IL-22 (a potent suppressor of oxidative stress) and whether HFDs exacerbated acute and chronic murine colitis. HFD modulated the differentiation and function of intestinal goblet cells via Kruppel-like Factor (KLF)-4 and down-regulation of Muc2 intestinal mucin. Long-term HFDs cause intestinal inflammation, ER stress and protein misfolding, which was resolved by IL-22 (2wk treatment). HFDs had no effect on the severity of acute DSS colitis, however, there was an increase in the rate of prolapse in chronic ER-stress-driven Winnie colitis. The effect of diet significantly alters mucosal immunity and influences gut barrier function.